Sphingosine-1-phosphate (S1P) having the structural formula represented by formula (A) is a lipid that is produced by the intracellular metabolic turnover of sphingolipids or the extracellular action of secretory sphingosine kinase. It is pointed out that S1P acts as an intercellular and intracellular messenger (Biochem. Pharm., 58, 201 (1999)).

As receptors of S1P, EDG-1 which is a G protein-coupled receptor and its analogous molecules, EDG-3, EDG-5, EDG-6 and EDG-8 (also called S1P1, S1P3, S1P2, S1P4 and S1P5, respectively) are known. They are called EDG receptor family together with EDG-2, EDG-4 and EDG-7 which are receptors of lysophosphatidic acid (LPA). S1P receptors binds to S1P and deliver signals into cells via G-protein coupled with the receptors. Gs, Gi, Gq and G12/13 are known as G-proteins to which S1P receptor can couple, and it is considered that the receptor relates to responses such as increase of cell proliferation, suppression of cell proliferation, induction of cell chemotaxis and inhibition of cell chemotaxis.
As biological action of S1P, inhibition of migration of smooth muscle cells or cancer cells, platelet aggregation, induction of cell chemotaxis, inhibition of cell chemotaxis and the like are known in vitro experiments, and as the results of in vivo experiments, it is known that S1P shows effects of controlling blood pressure, promoting angiogenesis, reducing renal blood flow, inhibiting lung fibrosis, promoting the lymphocyte homing into lymphatic organs and the like. It is considered that these various physiological effects are mediated by S1P receptors existing in cell membrane. However, it has been scarcely clarified excluding some cases which subtypes of S1P receptors mediate these effects in practice.
Recently, from the study for EDG-1 knock-out mice, it is strongly indicated that S1P induced angiogenesis via EDG-1 (Yujing Liu, et al., J. Clin. Invest., 106, 951 (2000)). Therefore, it is suggested that EDG-1 agonist is used as a treating agent for disease caused by anangioplasia. For example, it is used as an agent for prevention and/or treatment of peripheral arterial disease such as arteriosclerosis obliterans, thromboangiitis obliterans, Buerger's disease or diabetic neuropathy; varicose vein such as hemorrhoid, anal fissure, anal fistula; dissecting aneurysm of the aorta, sepsis, inflammatory disease such as angiitis, nephritis or pneumonia, various edematous disease caused by ischemia of various organ or increase of the blood permeability, for example, myocardial infarction, cerebral infarction, angina, DIC (disseminated intravascular coagulation), pleuritis, congestive heart failure or multiple organ failure. Furthermore, it is used as an accentuation agent for healing of wound in cornea, skin, digestive organs or the like, for example, an agent for prevention and/or treatment for bedsore, burn, chronic ulcerative colitis or Crohn's disease. In addition, it is used as a preoperative, postoperative and/or prognostic activator for blood vessel accompanying transplantation of various organs, for example, as an adhesion activator of transplanted organs such as heart transplantation, renal transplantation, dermal transplantation or liver transplantation.
Different from other EDG receptors, on the other hand, EDG-6 is localized and strongly expressed in cells of the lymphatic and hematopoietic systems including spleen, leukocytes, lymph gland, thymus, bone marrow, lung and the like, which suggests the possibility of closely relating to the effects of S1P in the course of inflammation or in the immune system (Biochem. Biophys. Res. Commun., 268, 583 (2000)).
Moreover, it is known that the EDG-6 polypeptide or its homolog is concerned with immunomodulation, antiinflammation and the like, which brings about the potential usability of these substances in treating autoimmune diseases (systemic lupus erythematosus, rheumatoid arthritis, myasthenia gravis and the like), allergic diseases (atopic dermatitis, asthma and the like), inflammation, infection, ulcer, lymphoma, malignant tumor, leukemia, arteriosclerosis, diseases associated with lymphocyte infiltration into a tissue and the like.
Accordingly, it appears that drugs acting against EDG-6 are useful as preventives and/or remedies for rejection in transplantation, rejection of a transplanted organ, transplantation versus host disease, autoimmune diseases (systemic lupus erythematosus, rheumatoid arthritis, myasthenia gravis and the like), allergic diseases (atopic dermatitis, asthma and the like), inflammation, infection, ulcer, lymphoma, malignant tumor, leukemia, arteriosclerosis, diseases associated with lymphocyte infiltration into a tissue and the like.
It is known that 2-amino-2-[2-(4-octylphenyl)ethyl]-1,3-propanediol hydrochloride (CAS Registration No. 162359-56-0, hereinafter referred to as “FTY720”) having a sphingosine-like structure has an immune suppressive effect. However, the target molecule thereof has remained unknown for a long time. Recently, it is clarified that FTY720 is phosphorylated in vivo and the phosphorylated FTY-720 binds to an S1P receptor (see Science, 296, 346 (2002); and J. Biol. Chem., 277, 21453 (2002)). As the results of detailed studies, it is found out that phosphorylated FTY720 binds to multiple subtypes of the S1P receptors, i.e., EDG-1, EDG-3, EDG-6 and EDG-8.
FTY720 is one of 2-amino-1,3-propanediol compounds represented by formula (Y):

wherein RY represents a linear or branched carbon chain which may have a substituent(s), aryl which may have a substituent(s), cycloalkyl which may have a substituent(s), etc; and R2Y, R3Y, R4Y and R5Y are the same or different and each represents a hydrogen atom, alkyl, aralkyl, acyl or alkoxycarbonyl (only necessary parts of the definitions of the symbols are extracted). It is disclosed that these compounds are useful as immunosuppressants (see WO 94/008943).
As the results of a recent clinical trial on FTY720 in human kidney transplantation, it is reported that FTY720 has an effect of significantly lowering the incidence rate of acute rejection. It is found out that FTY720 exerts the major effect of reducing the lymphocyte count in the peripheral blood without suppressing the proliferation or activation, the memory function and the ability to recognize a foreign matter in viral infection of lymphocytes. Thus, it is indicated that FTY720 is useful in treating diseases such as rejection in transplantation.
However, it is also reported that FTY720 has a side effect of causing bradycardia after administration (J. Am. Soc. Nephrol., 13, 1073 (2002)). Therefore, attention should be sufficiently given in using it. Accordingly, there has been required a highly safe drug which shows a high therapeutic effect and yet has little side effect.
Recently, it is reported that an EDG-1 agonist is useful as an immunosuppressant. However, it has never been stated that an EDG-6 agonist or antagonist is useful as an immunosuppressant (see WO 03/061567).
Moreover, it is disclosed that a compound represented by formula (S):

wherein ArS represents phenyl or naphthyl; AS represents carboxy, etc.; nS represents 2, 3 or 4; R1S and R2S each independently represents a hydrogen atom, a halogen atom, hydroxy, carboxy, C1-6 alkyl which may be substituted with 1 to 3 halogen atoms or phenyl which may be substituted with 1 to 3 halogen atoms; R3S represents a hydrogen atom or C1-4 alkyl which may be substituted with 1 to 3 hydroxy or halogen atoms; R4Ss each independently represents hydroxy, a halogen atom, carboxy, etc.; CS represents C1-8 alkyl, C1-8 alkoxy, phenyl, etc. or CS is nil; and BS represents phenyl, C5-16 alkyl, etc. (only necessary parts of the definitions of the symbols are extracted);
a pharmaceutically acceptable salt thereof and a hydrate thereof, and
a compound represented by formula (T):

wherein ArT represents phenyl or naphthyl; AT represents carboxy, etc.; mT represents 0 or 1; nT represents 0 or 1; R1T and R2T each independently represents a hydrogen atom, a halogen atom, hydroxy, carboxy, C1-4 alkyl or phenyl which may be substituted with a halogen atom, etc.; R3T represents a hydrogen atom, C1-4 alkyl which may be substituted with hydroxy or a halogen atom, etc.; R4T's each independently represents a halogen atom, C1-4 alkyl, C1-3 alkoxy, etc.; CT represents C1-8 alkyl, C1-8 alkoxy, phenyl, etc. or CT is nil; and BT represents phenyl, C5-16 alkyl, etc. (only necessary parts of the definitions of the symbols are extracted);
a pharmaceutically acceptable salt thereof and a hydrate thereof are useful as EDG-1 agonists (see WO 03/062248 and WO 03/062252).
Also, as an EDG-1 agonist, known is a carboxylic acid derivative represented by formula (Z):

wherein R1Z represents C1-8 alkyl, C1-8 alkoxy, a halogen atom, nitro or trifluoromethyl; ring AZ represents a C5-7 monocyclic carbocyclic group or a 5- to 7-membered monocyclic heterocyclic group containing one or two nitrogen atoms, one oxygen atom and/or one sulfur atom; EZ represents —CH2—, —O—, —S— or —NR6Z—, in which R6Z represents a hydrogen atom or C1-8 alkyl; R2Z represents C1-8 alkyl, C1-8 alkoxy, a halogen atom, nitro or trifluoromethyl; R3Z represents a hydrogen atom or C1-8 alkyl; R4Z represents a hydrogen atom or C1-8 alkyl, or R2Z and R4Z may be taken together to form —CH2CH2— or —CH═CH—; GZ represents —CONR7Z—, —NR7ZCO—, —SO2NR7Z—, —NR7ZSO2—, —CH2NR7Z— or —NR7ZCH2—, in which R7Z represents a hydrogen atom, C1-8 alkyl or the like; QZ represents C1-4 alkylene or the like; pZ represents 0 or an integer of 1 to 5; qZ represents an integer of 4 to 6; rZ represents 0 or an integer of 1 to 4;  represents a single bond or a double bond, a prodrug thereof or a non-toxic salt thereof (WO02/092068).